Effects of Canagliflozin in Patients with Baseline eGFR <30 ml/min per 1.73 m2: Subgroup Analysis of the Randomized CREDENCE Trial.

Abstract

BACKGROUND AND OBJECTIVES:

The Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial demonstrated that the sodium glucose cotransporter 2 (SGLT2) inhibitor canagliflozin reduced the risk of kidney failure and cardiovascular events in participants with type 2 diabetes mellitus and CKD. Little is known about the use of SGLT2 inhibitors in patients with eGFR <30 ml/min per 1.73 m2. The participants in the CREDENCE study had type 2 diabetes mellitus, a urinary albumin-creatinine ratio >300-5000 mg/g, and an eGFR of 30 to <90 ml/min per 1.73 m2 at screening. This post hoc analysis evaluated participants with eGFR <30 ml/min per 1.73 m2 at randomization.

DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS:

Effects of eGFR slope through week 130 were analyzed using a piecewise, linear, mixed-effects model. Efficacy was analyzed in the intention-to-treat population, on the basis of Cox proportional hazard models, and safety was analyzed in the on-treatment population. At randomization (an average of 29 days after screening), 174 of 4401 (4%) participants had an eGFR <30 ml/min per 1.73 m2 (mean [SD] eGFR, 26 [3] ml/min per 1.73 m2).

RESULTS:

From weeks 3 to 130, there was a 66% difference in the mean rate of eGFR decline with canagliflozin versus placebo (mean slopes, -1.30 versus -3.83 ml/min per 1.73 m2 per year; difference, -2.54 ml/min per 1.73 m2 per year; 95% confidence interval [CI], 0.90 to 4.17). Effects of canagliflozin on kidney, cardiovascular, and mortality outcomes were consistent for those with eGFR <30 and ≥30 ml/min per 1.73 m2 (all P interaction >0.20). The estimate for kidney failure in participants with eGFR <30 ml/min per 1.73 m2 (hazard ratio, 0.67; 95% CI, 0.35 to 1.27) was similar to those with eGFR ≥30 ml/min per 1.73 m2 (hazard ratio, 0.70; 95% CI, 0.54 to 0.91; P interaction=0.80). There was no imbalance in the rate of kidney-related adverse events or AKI associated with canagliflozin between participants with eGFR <30 and ≥30 ml/min per 1.73 m2 (all P interaction >0.12).

CONCLUSIONS:

This post hoc analysis suggests canagliflozin slowed progression of kidney disease, without increasing AKI, even in participants with eGFR <30 ml/min per 1.73 m2.

• Authors: George Bakris, Megumi Oshima, Kenneth W Mahaffey, Rajiv Agarwal, Christopher P Cannon, George Capuano, David M Charytan, Dick de Zeeuw, Robert Edwards, Tom Greene, Hiddo J L Heerspink, Adeera Levin, Bruce Neal, Richard Oh, Carol Pollock, Norman Rosenthal, David C Wheeler, Hong Zhang, Bernard Zinman, Meg J Jardine, Vlado Perkovic
• Journal: Clinical journal of the American Society of Nephrology : CJASN (Clin J Am Soc Nephrol) Vol. 15 Issue 12 Pg. 1705-1714 (12 07 2020) ISSN: 1555-905X [Electronic] United States
• PMID: 33214158 (Publication Type: Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 by the American Society of Nephrology.

Chemical References

• Sodium-Glucose Transporter 2 Inhibitors
• Canagliflozin

Topics

• Acute Kidney Injury (diagnosis, physiopathology, prevention & control)
• Aged
• Canagliflozin (adverse effects, therapeutic use)
• Diabetes Mellitus, Type 2 (blood, diagnosis, drug therapy)
• Diabetic Nephropathies (diagnosis, drug therapy, physiopathology)
• Disease Progression
• Double-Blind Method
• Female
• Glomerular Filtration Rate (drug effects)
• Humans
• Kidney (drug effects, physiopathology)
• Male
• Middle Aged
• Risk Factors
• Sodium-Glucose Transporter 2 Inhibitors (adverse effects, therapeutic use)
• Time Factors
• Treatment Outcome